NIROGACESTAT: 497 Adverse Event Reports & Safety Profile

OGSIVEO oral tablets contain nirogacestat (as nirogacestat hydrobromide), a gamma (ɣ) secretase inhibitor. Nirogacestat hydrobromide is chemically known as (S)-2-(((S)-6,8-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl) pentanamide dihydrobromide. The empirical formula is C 27 H 43 Br 2 F 2 N 5 O and the molecular weight is 651.48 g/mol. Nirogacestat hydrobromide is a white to off white powder with an aqueous solubility of 11.4 mg/mL and a pH of 4.4 in water at 25°C. Nirogacestat dihydrobromide is highly soluble at low pH, however the solubility significantly decreases at pH > 6.0. The molecule has pKa’s of 5.77 and 7.13. The structural formula for nirogacestat hydrobromide is: OGSIVEO (nirogacestat) tablets are immediate release (IR), film-coated tablets intended for oral administration.

Each

50 mg tablet contains 50 mg nirogacestat as 66.525 mg nirogacestat hydrobromide. OGSIVEO 50 mg tablets are round, biconvex with an approximate diameter of 8 mm. They are film coated, orange in color, and debossed with “50” on one face and plain on the other face.

Each

100 mg tablet contains 100 mg nirogacestat as 133.050 mg nirogacestat hydrobromide. OGSIVEO 100 mg tablets are round, biconvex with an approximate diameter of 10 mm. They are film coated, light orange in color, and debossed with “100” on one face and plain on the other face.

Each

150 mg tablet contains 150 mg nirogacestat as 199.574 mg nirogacestat hydrobromide. OGSIVEO 150 mg tablets are oval, biconvex with approximate dimensions of 8.5 X 17.5mm. They are film coated, orange yellow in color, and debossed with “150” on one face and plain on the other face. OGSIVEO tablets contain the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate type A. The tablets are finished with Opadry ® QX orange film coating consisting of the following ingredients: FD&C yellow #6/sunset yellow FCF aluminum lake, glycerol monocaprylocaprate type 1/mono/diglycerides, iron oxide yellow, macrogol (PEG) polyvinyl alcohol graft copolymer, polyvinyl alcohol – partially hydrolyzed, talc, and titanium dioxide. The structural formula for nirogacestat hydrobromide is: OGSIVEO oral tablets contain nirogacestat (as nirogacestat hydrobromide), a gamma (ɣ) secretase inhibitor. Nirogacestat hydrobromide is chemically known as (S)-2-(((S)-6,8-Difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl) pentanamide dihydrobromide. The empirical formula is C27H43Br2F2N5O and the molecular weight is 651.48 g/mol. Nirogacestat hydrobromide is a white to off white powder with an aqueous solubility of 11.4 mg/mL and a pH of 4.4 in water at 25C. Nirogacestat dihydrobromide is highly soluble at low pH, however the solubility significantly decreases at pH > 6.0. The molecule has pKa’s of 5.77 and 7.13.

AND USAGE OGSIVEO is indicated for adult patients with progressing desmoid tumors who require systemic treatment. OGSIVEO is a gamma secretase inhibitor indicated for adult patients with progressing desmoid tumors who require systemic treatment. ( 1 )

AND ADMINISTRATION The recommended dosage is 150 mg orally twice daily until disease progression or unacceptable toxicity. ( 2.1 )

See Full Prescribing

Information for dosage modifications due to adverse reactions. ( 2.2 )

2.1 Recommended Dosage The recommended dosage of OGSIVEO is 150 mg administered orally twice daily until disease progression or unacceptable toxicity.

Each

150 mg dose of OGSIVEO consists of three 50 mg tablets or one 150 mg tablet. OGSIVEO may be taken with or without food. Instruct patients to swallow OGSIVEO tablets whole and not to break, crush, or chew prior to swallowing. If a patient vomits or misses a dose, instruct the patient to take the next dose at its scheduled time.

2.2 Dos ag e Modifications for Adverse Reactions The recommended dose modifications for OGSIVEO for selected severe adverse reactions are summarized in Table 1 [ see Warnings and Precautions ( 5 ) , Adverse Reactions ( 6 ) ]. For other severe adverse reactions, life-threatening adverse reactions, or persistent intolerable Grade 2 adverse events, withhold drug until resolved to Grade ≤ 1 or baseline. Only restart at a dose of 100 mg twice daily after considering the potential benefit and likelihood of recurrence of the adverse reaction. Permanently discontinue OGSIVEO for recurrence of severe or life-threatening adverse reaction upon rechallenge at the reduced dose.

Table

1.

Recommended Dose

Modifications for Adverse Reactions Adverse Reaction Severity OGSIVEO Dosage Modifications Diarrhea persisting for ≥ 3 days despite maximal medical therapy [ see Warnings and Precautions ( 5.1 ) ]

Grades

3 or 4 Withhold OGSIVEO until resolved to Grade ≤ 1 or baseline, then restart at a dose of 100 mg twice daily. ALT or AST increased [see Warnings and Precautions ( 5.3 ) ]

Grade

2 (≥ 3 to 5 × ULN) Withhold OGSIVEO until ALT, AST, or both are resolved to < 3 × ULN or baseline, then restart at a dose of 100 mg twice daily.

Grades

3 or 4 (> 5 × ULN) Permanently discontinue. Hypophosphatemia persisting for ≥ 3 days despite maximal replacement therapy [see Warnings and Precautions ( 5.5 ) ]

Grades

3 or 4 Withhold OGSIVEO until resolved to Grade ≤ 1 or baseline, then restart at a dose of 100 mg twice daily. Hypokalemia despite maximal replacement therapy [see Warnings and Precautions ( 5.5 ) ]

Grades

3 or 4 Withhold OGSIVEO until resolved to Grade ≤ 1 or baseline, then restart at a dose of 100 mg twice daily.

None. None. ( 4 )

REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Diarrhea [ see Warnings and Precautions ( 5.1 )]

Ovarian

Toxicity [ see Warnings and Precautions ( 5.2 )] Hepatotoxicity [see Warnings and Precautions ( 5.3 )] Non-Melanoma Skin Cancers [see Warnings and Precautions ( 5.4 )]

Electrolyte

Abnormalities [ see Warnings and Precautions ( 5.5 )] The most common ( > 15 %) adverse reactions are diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection and dyspnea. ( 6.1 ) The most common laboratory abnormalities (≥15%) are decreased phosphate, increased urine glucose, increased urine protein, increased AST, increased ALT, and decreased potassium. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact SpringWorks Therapeutics at 1-888-400-7989 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of OGSIVEO was evaluated in 69 patients enrolled in DeFi with progressing desmoid tumor <span class="opacity-50 text-xs">[see Clinical Studies ( 14 ) ]</span>. Patients received OGSIVEO 150 mg orally twice daily or placebo orally twice daily until disease progression or unacceptable toxicity. The median duration of exposure to OGSIVEO was 20.6 months (range: 0.3 to 33.6). Serious adverse reactions occurred in 20% of patients who received OGSIVEO. Serious adverse reactions occurring in ≥ 2% of patients were ovarian toxicity (4%). Permanent discontinuation of OGSIVEO due to an adverse reaction occurred in 20% of patients. Adverse reactions which resulted in permanent discontinuation of OGSIVEO in ≥ 2% of patients were diarrhea, ovarian toxicity, increased ALT, and increased AST. Dosage interruptions of OGSIVEO due to an adverse reaction occurred in 51% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included diarrhea, rash, stomatitis, hypophosphatemia, fatigue, folliculitis, nausea, and ovarian toxicity. Dose reductions of OGSIVEO due to an adverse reaction occurred in 42% of patients. Adverse reactions which required dose reductions in ≥ 2% of patients included diarrhea, rash, stomatitis, hypophosphatemia, folliculitis, hidradenitis, and ovarian toxicity. The most common (≥ 15% with a difference between arms of ≥ 5% compared to placebo) adverse reactions that occurred in patients receiving OGSIVEO were diarrhea, ovarian toxicity, rash, nausea, fatigue, stomatitis, headache, abdominal pain, cough, alopecia, upper respiratory tract infection and dyspnea.

Table

2 summarizes the adverse reactions that occurred in DeFi.

Table

2.

Adverse

Reactions (≥ 15%) in Patients with Desmoid Tumor Who Received OGSIVEO with a Difference Between Arms of ≥ 5% Compared to Placebo on DeFi Adverse Reaction OGSIVEO (N = 69) Placebo (N = 72)

All

Grades (%)

Grade

3 (%)

All

Grades (%)

Grade

3 (%)

Gastrointestinal Diarrhea

84 16 35

1.4 Nausea 54 1.4 39 0 Stomatitis a 39 4 4 0 Abdominal Pain a 22 1.4 14

1.4 Reproductive S ystem Ovarian toxicity a , b 75 c 0 0 0 Skin and S ubcutaneous T issue Rash a 68 6 14 0 Alopecia 19 0 1.4 0 General Fatigue a 54 2.9 38 0 Nervous S ystem Headache a 30 0 15 0 Respiratory Cough a 20 0 6 0 Dyspnea 16 0 6 0 Infections Upper respiratory tract infection a 17 0 2.8 0 a Includes multiple related composite terms. b Investigator assessment of ovarian toxicity included ovarian failure, premature menopause, amenorrhea, and menopause c The number of females of reproductive potential in each arm is used as the denominator (OGSIVEO N = 36, Placebo N = 37) Clinically relevant adverse reactions occurring in &lt; 15% of patients receiving OGSIVEO in DeFi included non-melanoma skin cancers, epistaxis, hidradenitis suppurativa, folliculitis, and influenza-like illness.

Table

3 summarizes laboratory abnormalities in DeFi.

Table

3.

Laboratory

Abnormalities (≥15%) that Worsened from Baseline in Patients with Desmoid Tumor Who Received OGSIVEO in DeFi Laboratory Abnormality OGSIVEO Placebo All Grades (%)

Grade

3 or 4 (%)

All

Grades (%)

Grade

3 or 4 (%)

Chemistry

Decreased phosphate a ,b 65 Not Applicable 11 Not Applicable Increased urine glucose c ,d 51 Not Applicable 0 Not Applicable Increased urine protein c 40 0 25 0 Increased aspartate aminotransferase a 33 2.9 18

1.4 Increased alanine aminotransferase a 30 6 21

1.4 Decreased potassium a 22 1.4 4.2 0 a The denominator used to calculate the rate was 69 for nirogacestat and 72 for placebo based on the number of patients with a baseline value and at least one post-treatment value. b CTCAE Version 5.0 does not include numeric thresholds for grading of hypophosphatemia; all grades represent patients with lab value &lt; Lower Limit of Normal (LLN). c The denominator used to calculate the rate was 68 for nirogacestat and 69 for placebo based on the number of patients with a baseline value and at least one post-treatment value. d CTCAE Version 5.0 does not include numeric thresholds for grading of increased urine glucose.

AND PRECAUTIONS Diarrhea: Severe diarrhea can occur. Monitor and dose modify for Grade 3-4 diarrhea. ( 5.1 )

Ovarian

Toxicity: Female reproductive function and fertility may be impaired. Advise females of reproductive potential of the potential risk prior to treatment and monitor routinely. ( 5.2 ) Hepatotoxicity: Elevated AST and ALT can occur. Monitor AST and ALT regularly and modify dose as recommended. ( 5.3 ) Non-Melanoma Skin Cancers: Perform dermatologic examination prior to initiation of OGSIVEO and routinely during treatment. ( 5.4 )

Electrolyte

Abnormalities: Monitor phosphate and potassium regularly and modify dose as recommended. ( 5.5 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 )

5.1 Diarrhea Diarrhea, sometimes severe, can occur in patients treated with OGSIVEO <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 ) ]</span> . In DeFi, diarrhea occurred in 84% of patients treated with OGSIVEO, and included Grade 3 events in 16% of patients. Median time to first diarrhea event for patients treated with OGSIVEO was 9 days (range: 2 to 434 days). Monitor patients and manage using antidiarrheal medications. Modify dose as recommended [ see Dosage and Administration ( 2.2 ) ]. 5. 2 Ovarian Toxicity Female reproductive function and fertility may be impaired in patients being treated with OGSIVEO. Impact on fertility may depend on factors including the duration of therapy and the state of gonadal function at the time of treatment. The long-term effects of OGSIVEO on fertility have not been established. Advise patients on the potential risks for ovarian toxicity before initiating treatment with OGSIVEO [ see Use in Specific Populations ( 8.3 ) ]. Monitor patients for changes in menstrual cycle regularity or the development of symptoms of estrogen deficiency, including hot flashes, night sweats, and vaginal dryness. 5. 3 Hepatotoxicity ALT or AST elevations occurred in 30% and 33% of patients who received OGSIVEO in DeFi, respectively.

Grade

3 ALT or AST elevations (> 5 × ULN) occurred in 6% and 2.9% of patients, respectively [see Adverse Reactions ( 6.1 ) ] . Monitor liver function tests regularly and modify dose as recommended [see Dosage and Administration ( 2.2 ) ] . 5. 4 Non-Melanoma Skin Cancers New non-melanoma skin cancers can occur in patients treated with OGSIVEO. In DeFi, cutaneous squamous cell carcinoma and basal cell carcinoma occurred in 2.9% and 1.4% of patients, respectively [see Adverse Reactions ( 6.1 ) ]. Perform dermatologic evaluations prior to initiation of OGSIVEO and routinely during treatment. 5. 5 Electrolyte Abnormalities Electrolyte abnormalities can occur in patients treated with OGSIVEO. In DeFi, these included decreased phosphate (65%) and decreased potassium (22%). Phosphate <2 mg/dL occurred in 20% of patients who received OGSIVEO.

Grade

3 decreased potassium occurred in 1.4% of patients [ see A dverse Reactions ( 6.1 ) ] . Monitor phosphate and potassium levels regularly and supplement as necessary. Modify dose as recommended [see Dosage and Administration ( 2.2 ) ]. 5. 6 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, OGSIVEO can cause fetal harm when administered to pregnant women. Oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity and death at maternal exposures below the human exposure at the recommended dose of 150 mg twice daily. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment with OGSIVEO and for 1 week after the last dose [ see Use in Specific Populations ( 8.1 , 8.3 ) ].

INTERACTIONS Strong or moderate CYP3A inhibitors: Avoid concomitant use. ( 7.1 ) Strong or moderate CYP3A inducers: Avoid concomitant use. ( 7.1 ) Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors and H2-receptor antagonists. If concomitant use cannot be avoided, OGSIVEO administration can be staggered with antacids. ( 7.1 )

7.1 Effect s of Other Drugs on OGSIVEO Table 4. Effects of Other Drugs on OGSIVEO Strong or Moderate CYP3A Inhibitors Clinical Effect Nirogacestat is a CYP3A substrate. Strong or moderate CYP3A inhibitors increase nirogacestat exposure [ see Clinical Pharmacology ( 12.3 )] , which may increase the risk of OGSIVEO adverse reactions. Prevention or Management Avoid concomitant use of OGSIVEO with strong or moderate CYP3A inhibitors including grapefruit products, Seville oranges, and starfruit. Strong or Moderate CYP3A Inducers Clinical Effect Nirogacestat is a CYP3A substrate. Strong or moderate CYP3A inducers decrease serum nirogacestat exposure [ see Clinical Pharmacology ( 12.3 )] , which may reduce the effectiveness of OGSIVEO. Prevention or Management Avoid concomitant use of OGSIVEO with strong or moderate CYP3A inducers.

Gastric Acid Reducing Agents Clinical

Effect Nirogacestat is poorly soluble at pH ≥ 6. Gastric acid reducing agents may decrease serum nirogacestat exposure [see Clinical Pharmacology ( 12.3 )], which may reduce the effectiveness of OGSIVEO. Prevention or Management Avoid concomitant use with proton pump inhibitors and H2 blockers. If concomitant use cannot be avoided, OGSIVEO can be staggered with antacids (e.g., administer OGSIVEO 2 hours before or 2 hours after antacid use).

7.2 Effects of OGSIVEO on Other Drugs Table 5. Effects of OGSIVEO on Other Drugs Certain CYP3ASubstrates Clinical Effect Nirogacestat increases exposure of CYP3A substrates [ see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to these substrates. Prevention or Management Avoid concomitant use with CYP3A substrates where minimal concentration changes may lead to serious adverse reactions. Certain CYP2C19 Substrates Clinical Effect Nirogacestat decreases exposure of CYP2C19 substrates <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>, which may decrease efficacy of these substrates. Prevention or Management Avoid concomitant use with OGSIVEO where decreased concentrations of CYP2C19 substrates may lead to significant decreases in efficacy of the CYP2C19 substrate unless otherwise recommended in the Prescribing Information for the CYP2C19 substrate.